Allylic alcohols: Valuable synthetic equivalents of non-activated alkenes in gold-catalyzed enantioselective alkylation of indoles

Article abstract of DOI:10.1016/j.jorganchem.2010.09.065

The recent booming of gold catalysis has demonstrated that unprecedented transformations can be realized in a highly selective manner. Moreover, due to the growing availability of chiral organic ligands, gold-catalysis can be considered as one of most dyn

Full text of DOI:10.1016/j.jorganchem.2010.09.065

Journal of Organometallic Chemistry 696 (2011) 338e347
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Allylic alcohols: Valuable synthetic equivalents of non-activated alkenes in
gold-catalyzed enantioselective alkylation of indoles
*
Marco Bandini , Andrea Gualandi, Magda Monari, Alessandro Romaniello, Diego Savoia, Michele Tragni
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The recent booming of gold catalysis has demonstrated that unprecedented transformations can be
realized in a highly selective manner. Moreover, due to the growing availability of chiral organic ligands,
gold-catalysis can be considered as one of most dynamic hot spots in asymmetric synthesis. However, in
this context, the use of non-activated olefinic CeC double bonds is still largely unexplored due to the
intrinsic inertness of C]C (respect to allenes and alkynes) in taking part in nucleophilic additions
Received 30 August 2010
Received in revised form
26 September 2010
Accepted 27 September 2010
Available online 7 October 2010
assisted by
p-electrophilic activations. Allylic alcohols have been demonstrated to be feasible “surro-
gates” of non-activated alkenes for the enantioselective allylic alkylation of indoles catalyzed by chiral
gold(I) complexes. In this investigation, a full account addressing efficiency and substrate scope of such
a process is presented.
Keywords:
Allylic alcohols
FriedeleCrafts reaction
Gold-catalysis
Indole
Ó 2010 Elsevier B.V. All rights reserved.
Stereoselection
1. Introduction
However, differently by alkynyl and allenic frameworks, the
stereoselective gold-catalyzed manipulation of non-activated
The use of gold(I)-catalysis in organic transformations has
unquestionably entered its golden age upon the exponential
growth observed over the last decade [1]. This widespread interest
is primarily ascribable to a number of unique properties featured
by [Au(I)] species, such as: functional group/moisture tolerance,
mildness of operating conditions, isohypticity (i.e. stability towards
olefins is still largely unexplored, due to their intrinsic inertness in
taking part to nucleophilic additions [2b]. In fact, although several
reports have efficiently addressed the gold-catalyzed activation of
alkynes or allenes toward nucleophiles, the enantioselective gold-
assisted electrophilic activation of olefins has been relatively poorly
documented. In this context, worth mentioning is the elegant
report by Widenhoefer and coworkers on the intermolecular
hydroamination of 1-alkenes with ureas in the presence of chiral
gold(I) complexes [3].
Related to this topic, we recently discovered that configura-
tionally defined allylic alcohols can be used as effective synthetic
equivalents of non-activated alkenes in stereoselective intra-
molecular allylic alkylation of indoles [4]. The reaction documented
for the first time the direct gold(I)-catalyzed activation of alcohols
in FriedeleCrafts-type alkylation (FCA) reactions and it represents
a reliable alternative to the stereoselective TsujieTrost-type allylic
alkylation of arenes [5]. It is noteworthy that, in terms of substrate
availability and sustainability the direct employment of allylic
alcohols is convenient because water is the only by-product of the
alkylating event. Instead, the Pd/Ir/Mo-assisted methodologies
require pre-installed [6] or in situ formed [7] leaving groups at the
allylic positions in the prochiral electrophilic substrates, that are
generally prepared from allylic alcohols.
oxido-reductive processes) and dual-function acidity (
s and p).
Furthermore, the large availability of chiral organic ligands concurs
to define Au(I)-catalysis as one of the most dynamic hot spots in
asymmetric synthesis [2].
The well-recognized carbophilicity of “soft” gold species has
been widely utilized in electrophilic activation of
p-electron-con-
taining compounds (e.g. alkenes, alkynes, allenes) toward nucleo-
philic attack. Worth mentioning, the high level of chemo- and
regioselectivity of these processes is rapidly revolutionizing the
synthetic portfolio for the functionalization of activated as well as
non-activated
p-systems, by focusing on critical issues such as:
mildness of experimental conditions, broadness of scope, atom
economy and tolerance of functional groups.
* Corresponding author. Tel.: þ39 051 209 9751; fax: þ39 051 209 9456.
E-mail address: marco.bandini@unibo.it (M. Bandini).
URL: http://www.mbandini-group.com
In this context, we envisioned that the aptitude of gold(I) species
to be involved in C]C electrophilic activation and the concomitant
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.09.065

M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
339
chelating coordination mode of chiral dinuclear gold complexes with
the allylic alcohols could satisfy the mandatory requirements to
obtain high levels of chemo- and stereoselectivity [8].
As a part of our ongoing research on the design and develop-
ment of new catalytic and stereoselective methodologies for the
decoration of arenes [9,10], we present here a full account on the use
of chiral gold(I)
p-Lewis acids for the enantioselective synthesis of
vinyl-tetrahydro-
b
-carbazoles and tetrahydro- -carbolines by
b
means of direct alkylation of indoles with allylic alcohols [11].
2. Result and discussion
2.1. Working plan
Functionalized tetrahydrocarbazoles (THCs) [12] A and tetra-
hydro-b-carbolines (THBCs) [13] B are key molecular motifs
frequently encountered in natural occurring polycyclic fused
indolyl-based alkaloids (Fig. 1) [14]. Nowadays, a variety of
synthetic methodologies for their preparation is available, [15]
however, the stringent request for more simple, selective and
sustainable synthetic routes justifies the ongoing interest of the
scientific community in the field.
Scheme 1. Synthesis of indolyl malonates 1,2 and indolyl methansulfonamides 3a,4a.
Our working plan to these classes of compounds relies on the
gold-catalyzed intramolecular FC-type alkylation of the indolyl
nucleus with allylic alcohols, that results in the introduction of
[16], the methansulfonamides were obtained by the coupling of the
indolyl 2- or 3-carboxaldehydes and TsNH2 (Ti(OEt)4, toluene,
reflux) [17] followed by reduction with NaBH4 (THF, 0 ꢀC / rt).
The indolyl derivatives 1e4 were then coupled with (Z)- or
(E)-allylic bromides C under basic conditions (NaH, THF, reflux),
then conventional removal of the protecting group (TBAF, THF,
a synthetically flexible vinyl group at the benzylic position (a or d).
Moreover, the transfer of chirality from enantiomerically pure
dinuclear gold(I) complexes of general formula [(PP)*(Au2X2)]
((PP)*: chiral C2-symmetric biphosphine ligand) to the final poly-
cyclic compounds would give access to stereochemically defined
molecular architectures.
0
ꢀC / rt) afforded the corresponding indolyl-substituted allylic
alcohols 5e8 in moderate yields (Scheme 2).
2.2. Synthesis of the acyclic precursors
2.3. Gold-catalyzed ring-closure
At the outset of our investigation, we reasoned that the
synthesis of configurationally pure allylic alcohol precursors was
essential to pursue the final aim due to the prochiral nature of the
C]C bond framework. To this aim, we excluded the use of poorly
stereoselective C]C bond synthetic methodologies such as Wittig-
type condensations or cross-metathesis reactions and we opted to
install the pre-formed olefin moieties to properly functionalized
indolyl cores. In particular, we identified in the readily available
indolyl malonates 1, 2 and indolyl methansulfonamides 3a,4a as
valuable building blocks for the FC-precursors (Scheme 1). Here,
while the malonates 1,2 were synthetized as previously described
In order to evaluate the applicability of asymmetric gold catal-
ysis to the planned cyclization, we selected compounds 5a and 8a
(Scheme 2) as model substrates, on which a survey of reaction
conditions (ligand, gold-source, counterion) was undertaken.
First,
a range of chiral C2 symmetric phosphine ligands
(L1eL10, Chart 1) were considered in promoting the ring-closure of
5a in the presence of dinuclear gold complexes made from [AuCl
(SMe2)] and representative results are collected in Table 1.
As emerging from Table 1, good to high isolated yields were
obtained (66e96%, excepted for DIOP L5, entry 5) working in
toluene as the solvent at room temperature. However, it turned
Scheme 2. Synthesis of C-2/3 tethered indolyl-allylic alcohols 5ae8a with allyl
bromides C.
Fig. 1. Target compounds (A,B) and working plan.

340
M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
the reaction mixture no significant variations with respect to the
best results were recorded (9a: yield ¼ 69%, ee ¼ 87%).
2.4. Scope and limitations of the catalytic protocol
The previously described outcomes of the FC-type reactions
demonstrated that the best catalytic system (L10(AuOTf)2, rt, 0 ꢀC,
toluene) proved generality for the synthesis of 1-vinyl- and
4-vinyltetrahydrocarbazoles in good extent. In particular, tolerance
toward a wide range of functional groups (EWG and EDG) on the
indole moiety was demonstrated and the desired 1-vinyl-THCs
9bei were isolated in 52e91% yield and ee of 80e96% (Fig. 2).
Worth mentioning, the presence of a methyl group at the indole
nitrogen prevented the ring-closing FriedeleCrafts alkylation,
probably due to the detrimental sterical hindrance induced by the
methyl group nearby the cyclization site (C2-position). The alkyl
substituents of the ester functions (i.e. Me, tBu, 5h,i) did not
significantly affect the chemical and stereochemical outcome,
providing THCs with ee of 85% and 92%, respectively.
Chart 1.
The methodology was then efficiently utilized for the FC-type
alkylation of indolyl-alcohols 6aee bearing the unsaturated side-
chain at the indole-C2 position. From the data depicted in Table 2
it turns out that the level of stereodifferentiation recorded in
the formation of compounds 10aee (ee ¼ 74e86%) was still
synthetically interesting, although slightly lower than that of
1-vinyl-THCs 9.
out that (S)-3,5-tBu-4-MeO-MeOBIPHEP L10 proved to be the
best ligand, leading to 1-vinyl-THC 9a in 78% yield and ee ¼ 88%
(entry 10). Then, the role of the counterion was proved to be
crucial for both reaction rate and stereoinduction, with OTfꢁ (tri-
fluoromethanesulfonate) acting as the best counterion (entries
10e14). Moreover, by lowering the reaction temperature to 0 ꢀC the
enantiomeric excess increased up to 90%, meanwhile a high yield
(95%) was obtained after 48 h (entry 15). Finally, it should be
observed that pre-formed [18] or in situ assembled L10-(Au2Cl2)
complex furnished comparable chemical outcomes (entry 15 vs
entry 16) and when insoluble AgCl was removed by filtration from
Although the synthesis of 4-vinyltetrahydro-b-carbolines 12
have been already addressed in our previous research projects,
up to now, catalytic enantioselective methodologies have relied
only on enantioselective Pd-catalyzed TsujieTrost allylic alkylation
with carbonates [6a] or gold-catalyzed diastereoselective cycliza-
tions (Scheme 3a and b) [19].
The results listed in Tables 2 and 3 prompted us to verify the
extension of the protocol to the preparation of analogous polycyclic
indolyl compounds bearing nitrogen atoms as tethering frame-
works. To this aim model substrate (Z)-8a was obtained in
straightforward manner through the synthetic route depicted in
Scheme 2. Interestingly, treating 8a under optimal reaction
parameters, (S)-3,5-tBu-4-MeO-MeOBIPHEP L10 and (S)-xylyl-
phanephos L3 provided 12a to a synthetically useful extent
(yield ¼ 71%/ee ¼ 80% with L3 and yield ¼ 75%/ee ¼ 80% with L10).
On the contrary, other C2-symmetric phosphine ligands (i.e. L1 and
L2) proved to be less efficient (entries 1,2, Table 3).
Table 1
Optimization of the reaction conditions for the intramolecular asymmetric allylic
alkylation of (Z)-5a.
The scope of the reaction was then investigated with a range of
(Z)-alcohols 8bee. Tolerance toward molecular functionalities on
the indolyl ring was demonstrated with enantiomeric excesses
ranking between 70% and 80%. Moreover, easily removable N
(1)-allyl group [20] was also introduced into the alcoholic precursor
(8f) and the corresponding THBC 12f was obtained in comparable
ee (78%, entry 10).
Interestingly, the configuration of the CeC double bond of
the acyclic precursor played a key role both on the malonate and
nitrogen-tethered substrates. As a matter of fact, allylic alcohols
(E)-5a and (E)-8a were completely inert toward the cyclization
conditions, probably due to an unfavorable spatial arrangement of
the sterically demanding bimetallic catalyst. Such an evidence
invokes a substrate-controlled mechanism, which is analogous to
the gold-catalyzed hydroindolination of allenes [21].
Entrya
L
AgX
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgBF4
AgSbF6
AgOTs
AgNTf2
AgOTf
AgOTf
72
85
90
95
8
95
95
77
73
78
55
25
10
95
95
84
ꢁ30
9
28
29
0
0
72
35
48
88
87
62
92
65
90
ꢁ90
9
L9
10
11
12
13
14
15d
16d,e
(R)-L10
(R)-L10
(R)-L10
(R)-L10
(R)-L10
(R)-L10
(S)-L10
Unfortunately, the methodology did not provide any encour-
aging result when applied to the synthesis of 1-vinyl-tetrahydro-g-
a
All the reactions were carried out in anhydrous toluene, under nitrogen atmo-
sphere, pre-forming the catalyst in CH2Cl2. L/[Au]/[Ag]: 10/20/20 mol%, unless
otherwise specified.
carbolines (THGCs). In fact, despite the numerous attempts, the
cyclization of C3-substituted indolyl alcohol (Z)-7a failed in
providing the desired THGC. The partial recovering of the starting
material with the concomitant formation of substantial amount of
unknown polymeric material was recorded (Scheme 4).
b
Isolated yield after flash chromatographic purification.
Determined by HPLC analysis with chiral column.
At 0 ꢀC, 48 h reaction time.
c
d
e
Isolated L10-(Au2Cl2) complex was employed.

M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
341
Fig. 2. Collection of 1-vinyl-THCs prepared by means of gold(I)-catalyzed allylic alkylation.
2.5. Determination of the absolute configuration
configuration of 10b was determined to be S, and the configurations
of 10a,cee assigned by analogy (Scheme 5).
The absolute configuration of tetrahydrocarbazole 10b and tet-
rahydro-b-carboline 12b were unambiguously determined via
chemical correlation and X-ray crystallography, respectively.
In particular, the vinyl group of the compound 10b (ee ¼ 80%)
was reduced under heterogeneously Pd-catalyzed hydrogenation
Analogously, absolute configuration of THBCs 12b was deter-
mined to be S by subjecting the THBC to single crystal crystallo-
graphic analysis (Fig. 3). Configurations of compounds 12a,cef
were assigned by analogy.
reaction to the corresponding
d
-ethyl-THC 10f (yield ¼ 85%,
2.6. Mechanistic discussion
ee ¼ 74%), and the optical rotation value compared with that of
the known compound [22]. In such
a way, the absolute
Due to the intrinsic “chelating” architecture of the allylic
alcohol, featuring a soft
p-base center (CeC double bond) and
Table 2
Catalytic enantioselective intramolecular FCA reactions. Synthesis of 4-vinyl-
tetrahydrocarbazoles 10.
Entrya
Alcohol
R/R1
Product
Yield (%)b
ee (%)c
1
6a
6b
6c
6d
6e
Et/H
10a
10b
10c
10d
10e
79
80
87
55
87
86
80
74
83
80
2d
3
tBu/H
Me/H
Et/OMe
Et/Me
4
5
a
All the reactions were carried out in anhydrous toluene under nitrogen atmo-
sphere, pre-forming the catalyst in CH2Cl2 (L10/[Au]/[Ag]: 10/20/20 mol%).
b
Isolated yield after flash chromatographic purification.
Determined by HPLC analysis with chiral column.
Room temperature.
c
Scheme 3. (a) Enantioselective Pd-catalyzed allylic alkylation of indoles. (b) Diaster-
eoselective gold-catalyzed synthesis of THBCs.
d

342
M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
Table 3
Intramolecular asymmetric allylic alkylation of 8a-f.
Entrya
L
Reagent
R/R1
Product
Yield (%)b
ee (%)c
1
2
3
L1
L2
L3
(S)-L10
(S)-L10
(S)-L10
(S)-L10
(S)-L10
(S)-L10
(S)-L10
(Z)-8a
(Z)-8a
(Z)-8a
(Z)-8a
(Z)-8a
(Z)-8b
(Z)-8c
(Z)-8d
(Z)-8e
(Z)-8f
H/Me
H/Me
H/Me
H/Me
H/Me
Cl/Me
Me/Me
OMe/Me
H/Bn
12a
12a
12a
12a
12a
12b
12c
12d
12e
12f
72
50
71
75
62
93
75
61
95
72
40 (R)
56
80
80
68
79
80
76
70
78
Fig. 3. ORTEP drawing of (S)-12b.
4
5d
6
7
8
9
10
spatial arrangement between the indolyl-alcohols and dinuclear
gold complex. Moreover, in a model cyclization process (L10-
(Au2Cl2) 50 mol%) with the O-capped substrate (Z)-5k (O-
TBDMS-5a), that would inhibit an effective AueOH contact, the
reaction rate was significantly lower (conv. 48%, ee ¼ 56%, 24 h).
Interestingly, the unreacted 5a was recovered with complete
inverted E-configuration of the double bond, that is ascribable to
H/allyl
a
All the reactions were carried out in anhydrous toluene, under nitrogen atmo-
sphere (L/[Au]/[Ag]: 10/20/20 mol%). The catalytic complex was pre-formed in
CH2Cl2 with [AuCl(SMe2)].
b
Isolated yield after flash chromatographic purification.
Determined by HPLC analysis on a chiral column.
At 0 ꢀC, 48 h reaction time.
c
d
a gold-promoted auration/rotation/deauration event of the
alkene function. It could be argued that the failure recorded with
5k might be due to the presence of a sterically demanding silyl
group in proximity of the allylic moiety, that would deny
a competent electrophilic activation of the CeC double bond.
However, even when more accessible indolyl methylether (Z)-5l
was utilized as the substrate, the desired THC 9a was isolated
only in traces.
All these evidences emphasized the importance of the free OH
function in controlling both the chemical and stereochemical
courses of the process. Although a conclusive rational to this
phenomena is not available yet, it is reasonable to assume the
presence of a chelating arrangement of allylic framework over the
dinuclear gold complex by means of bridging counterion effect
(eOH/X/Au). However, the possibility that the second gold atom
could act as a mere spectator, perhaps stabilizing the organogold
intermediates through aurophilic interactions, cannot be ruled out
at the present.
Finally, the complementarity of the [Au(I)]-catalyzed nucleo-
philic allylic substitution to the [Pd(0)/(II)] analogues, [6a] was
demonstrated by synthesizing and subjecting to ring-closing
event the indolyl acetate 5m carrying an efficient leaving group
at the allylic position. Interestingly, under optimal reaction
parameters, 9a was obtained only in poor extent (36% yield) and
with synthetically unacceptable enantiomeric excess (15%,
Scheme 6).
Scheme 4. Attempted gold-catalyzed synthesis of THGC derivatives.
a hard s-base unit (hydroxyl group) adjacent in space, two possible
coordination modes can be envisaged with dinuclear cationic gold
complexes like L10-(Au2OTf2): a) single-site interaction, involving an
Au/C]C bond interaction, and b) chelating-like modality, in which
the mandatory Au/C]C interaction is accompanied by an addi-
tional contact involving the hydroxyl group and the second gold
atom.
Preliminary insight into the activation mode came from the
prominent role of the configuration of the CeC double bond over
the chemical output (vide infra). This finding supports a direct
engagement of the hydroxyl group in the catalytically active
3. Conclusion
In conclusion, we have demonstrated the efficiency of (Z)-allylic
alcohols as alkylating agents in the Au-catalyzed enantioselective
FC-type reaction of indoles. The method exploits the
Scheme 6. Model substrates poorly reactive in the Au-catalyzed cyclization
(E ¼ CO2Et).
Scheme 5. Determination of the absolute configuration of 10b.

M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
343
Table 4
unprecedentedly reported capability of chiral gold(I) catalysts to
activate directly and selectively prochiral -activated (Z)-allylic
Crystal data and structure refinement for 12b.
p
alcohols toward nucleophilic substitution in highly enantiose-
lective manner. This methodology opens a route to enantiomeri-
cally enriched functionalized THBCs and THCs.
Compound
12b
Formula
M
T, K
C21H21ClN2O2S
400.91
296(2)
Crystal symmetry
Space group
a, Å
b, Å
c, Å
Orthorhombic
P212121
7.969(2)
10.659(4)
23.880(6)
90
90
90
2028(1)
4
1.313
0.309
840
0.10 ꢂ 0.15 ꢂ 0.20
2.09e23.40
13,929
4. Experimental
4.1. General details
ꢀ
ꢀ
ꢀ
a
,
1H NMR spectra were recorded on Varian 200 (200 MHz), Varian
400 (400 MHz) spectrometers. Chemical shifts are reported in ppm
from TMS with the solvent resonance as the internal standard
b
,
g
,
V, Å3
Z
Dc, Mg mꢁ3
(deuterochloroform:
d 7.27 ppm). Data are reported as follows:
), mmꢁ1
chemical shift, multiplicity (s ¼ singlet, d ¼ duplet, t ¼ triplet,
q ¼ quartet, bs ¼ broad singlet, m ¼ multiplet), coupling constants
(Hz), number of protons. 13C NMR spectra were recorded on a Var-
ian 200 (50 MHz), Varian 400 (100 MHz) spectrometers with
complete proton decoupling. Chemical shifts are reported in ppm
from TMS with the solvent as the internal standard (deutero-
m
(Mo-K
a
F(000)
Crystal size, mm
ꢀ
q
limits,
Reflections collected
Unique obs. reflections [Fo > 4
s
(Fo)]
2902 [R(int) ¼ 0.0466]
Goodness-of-fit-on F2
1.029
R
1 (F)a, wR2 (F2)b
0.0346, 0.0801
0.153 and ꢁ0.189
chloroform:
d 77.0 ppm). GCeMS spectra were taken by EI ioniza-
Largest diff. peak and hole, e Åꢁ3
tion at 70 eV on a HewlettePackard 5971 with GC injection. They
are reported as: m/z (rel. intense). LC-electrospray ionization
mass spectra were obtained with Agilent Technologies MSD1100
single-quadrupole mass spectrometer. Chromatographic purifica-
tion was done with 240e400 mesh silica gel. Analytical high
performance liquid chromatography (HPLC) was performed on
a liquid chromatograph equipped with a variable wave-length UV
detector (deuterium lamp 190e600 nm), using Daicel ChiracelÔ
OD and AD columns (0.46 cm I.D. ꢂ 25 cm) (Daicel Inc). HPLC
grade isopropanol and hexane were used as the eluting solvents.
Optical rotations were determined in a 1 mL cell with a path length
of 10 mm (NaD line). Melting points were determined with Bibby
Stuart Scientific Melting Point Apparatus SMP 3 and are not cor-
rected. For analytic characterization of compounds 5aek, 6aee,
9aei and 10aee see Ref. [4]. The X-ray intensity data for 12b were
measured on a Bruker SMART Apex diffractometer equipped with
P
P
a
R1
wR2
¼
jjFoj ꢁ jFcjj= jFoj.
P
P
wðFo2 ꢁ Fc2Þ2= wðFo2Þ2ꢃ1=2 where w
b
¼
¼
½
¼
1=½s2ðFo2Þ þ ðaPÞ2 þ bPꢃ
where P
ðFo2 þ Fc2Þ=3.
added and the mixture refluxed for 4 h. Then, after cooling at
rt, the solvent was evaporated. The residue was dissolved in
MeOH (10 mL) and THF (10 mL) and NaBH4 (9.7 mmol) was slowly
added at 0 ꢀC. After 4 h stirring at room temperature, water
(0.5 mL) was slowly added at 0 ꢀC and the solvent was evaporated.
Finally, the product was purified by flash column chromatography
(SiO2) to give the corresponding tosyl amide 3a/4.
4.2.1. N-((1H-Indol-3-yl)methyl)-4-methylbenzenesulfonamide
(3a)
Yield ¼ 81%. Flash chromatography (c-Hex:AcOEt ¼ 70:30); light
a CCD area detector and a graphite monochromated Mo-K
a radia-
red solid; m.p. ¼ 151.4e152.1 ꢀC; 1H NMR (400 MHz, CDCl3):
tion source (
l
¼ 0.71073 Å). Cell dimensions and the orientation
d
¼ 8.06 (bs, 1H), 7.80 (d, J ¼ 8.8 Hz, 2H), 7.41 (m, 1H), 7.35 (m, 1H),
matrix were initially determined from a least-squares refinement
on reflections measured in three sets of 20 exposures, collected in
7.32 (d, J ¼ 8.8 Hz, 2H), 7.21 (ddd, J ¼ 1.4 Hz, J ¼ 7.2 Hz, J ¼ 8.4 Hz,
1H), 7.09 (ddd, J ¼ 1.1 Hz, J ¼ 7.2 Hz, J ¼ 8.0 Hz, 1H), 7.05 (m, 1H),
4.47 (t, J ¼ 5.3 Hz, 1H), 4.34 (d, J ¼ 5.3 Hz, 2H), 2.46 (s, 3H); 13C NMR
three different
For all crystals, a full sphere of reciprocal space was scanned by
0.3ꢀ
steps. The software SMART [23a] was used for collecting
u regions, and eventually refined against all data.
(100 MHz, CDCl3):
d
¼ 143.4, 136.8, 136.2, 129.7 (2C), 127.5 (2C),
u
126.1, 123.3, 122.6, 120.0, 118.6, 111.3, 111.0, 40.0, 29.7, 21.3; MS (ES):
frames of data, indexing reflections and determination of lattice
parameters. The collected frames were then processed for inte-
gration by software SAINT [23a] and an empirical absorption
correction was applied with SADABS [23b]. The structure was
solved by direct methods (SIR 97) [23c] and subsequent Fourier
syntheses and refined by full-matrix least-squares calculations on
F2 (SHELXTL) [24] attributing anisotropic thermal parameters to the
non-hydrogen atoms. All hydrogen atoms were located in the
Fourier map. The aromatic, methyl, methylene and vinyl hydrogen
atoms were placed in calculated positions, refined with isotropic
thermal parameters U(H) ¼ 1.2 Ueq(C) or U(H) ¼ 1.5 Ueq(C-Me), and
allowed to ride on their carrier carbons whereas the methine H
atom was located in the Fourier map and refined isotropically [U
(H) ¼ 1.2 Ueq(C)]. Table 4.
m/z ¼ 323.0 [M þ Na]þ.
4.2.2 N-((1-Methyl-indol-2-yl)methyl-4-methyl-
benzenesulfonamide (4a)
Yield ¼ 79%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
white solid. m.p. ¼ 146.3e147.2 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼ 7.77 (dt, J ¼ 1.6 Hz, J ¼ 8.4 Hz, 2H), 7.52 (dt, J ¼ 0.8 Hz, J ¼ 8.0 Hz,
1H), 7.31 (dt, J ¼ 1.6 Hz, J ¼ 8.4 Hz, 1H), 7.28 (m, 1H), 7.23 (ddd,
J ¼ 1.2 Hz, J ¼ 6.6 Hz, J ¼ 9.2 Hz, 1H), 7.09 (ddd, J ¼ 1.2 Hz, J ¼ 6.6 Hz,
J ¼ 8.0 Hz,1H), 6.31 (s,1H), 4.53 (t, J ¼ 6.0 Hz,1H), 4.28 (d, J ¼ 6.0 Hz,
2H), 3.71 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 143.8,
138.0, 136.3, 133.3, 129.8 (2C), 127.1 (2C), 126.9, 122.1, 120.6, 119.7,
109.2, 102.4, 40.0, 29.8, 21.5; MS (ES): m/z ¼ 315.0 [M þ H]þ, 337.1
[M þ Na]þ.
4.2. General procedure for the synthesis of indole-
methansulfonamides (3a/4)
4.2.3. N-((5-Chloro-1-methyl-indol-2-yl)methyl)-4-
methylbenzenesulfonamide (4b)
Yield ¼ 68%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
To a solution of indole carboxaldehyde (2.4 mmol) in toluene
(10 mL), tosyl amide (3.6 mmol) and Ti(OEt)4 (4.8 mmol) were
white solid. m.p. ¼ 130.5e131.5 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼ 7.76 (d, J ¼ 7.8 Hz, 2H), 7.48 (m, 1H), 7.32 (d, J ¼ 7.8 Hz, 2H), 7.17

344
M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
(m, 2H), 6.25 (s, 1H), 4.53 (d, J ¼ 7.1 Hz, 1H), 4.21 (d, J ¼ 7.1 Hz, 2H),
3.71 (s, 3H), 2.44 (s, 3H); MS (EI): m/z ¼ 191 (100), 178 (42), 348
(38), 91 (36).
solvents was evaporated to give a yellow slurry. Two-steps overall
yields are given.
4.3.1. (Z)-7a
4.2.4. N-((1,5-Dimethyl-indol-2-yl)methyl)-4-
methylbenzenesulfonamide (4c)
Yield ¼ 45%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
white solid. m.p. ¼ 128.7e129.4 ꢀC; 1H NMR (400 MHz, CDCl3):
Yield ¼ 79%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
d
¼ 8.19 (bs, 1H), 7.80 (d, J ¼ 8.1 Hz, 2H), 7.66 (d, J ¼ 8.1 Hz, 1H), 7.38
yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼ 7.76e7.80 (m, 3H), 7.31
(dt, J ¼ 0.8 Hz, J ¼ 8.2 Hz, 1H), 7.34 (d, J ¼ 8.1 Hz, 1H), 7.22 (ddd,
J ¼ 1.1 Hz, J ¼ 7.0 Hz, J ¼ 8.2 Hz, 1H), 7.10 (ddd, J ¼ 1.1 Hz, J ¼ 7.0 Hz,
J ¼ 8.0 Hz, 1H), 7.02 (d, J ¼ 2.4 Hz, 1H), 5.54 (m, 1H), 5.25 (m, 1H),
4.55 (s, 3H), 3.84 (t, J ¼ 5.6 Hz, 1H), 3.82 (dd, J ¼ 1.4 Hz,
(m, 2H), 7.16 (d, J ¼ 8.4 Hz, 1H), 7.04 (dd, J ¼ 1.3 Hz, J ¼ 8.4 Hz, 1H),
6.21 (s, 1H), 4.64 (bs, 1H), 4.26 (d, J ¼ 6.1 Hz, 2H), 3.68 (s, 3H), 2.44
(s, 3H), 2.42 (s, 3H); MS (EI): m/z ¼ 171 (100), 158 (55), 91 (49), 328
(41), 144 (35), 207 (28).
J ¼ 7.9 Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 145.0,
143.4, 137.0, 131.6, 129.8 (2C), 127.4 (2C), 126.8, 124.3, 122.6, 120.0,
119.2, 111.3, 110.3, 108.7, 57.9, 43.1, 42.9, 21.5; MS (ES): m/z ¼ 393.0
[M þ Na]þ.
4.2.5. N-((5-Methoxy-1-methy-indol-2-yl)methyl)-4-
methylbenzenesulfonamide (4d)
Yield ¼ 73%. Flash chromatography (c-Hex:AcOEt ¼ 60:40);
white solid. m.p. ¼ 136.7e137.2 ꢀC; 1H NMR (400 MHz, CDCl3):
4.3.2. (Z)-8a
d
¼ 7.72 (d, J ¼ 8.0 Hz, 2H), 7.26 (d, J ¼ 8.0 Hz, 2H), 7.12 (d, J ¼ 9.0 Hz,
Yield ¼ 68%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
1H), 6.95 (d, J ¼ 2.0 Hz, 1H), 6.85 (dd, J ¼ 2.0 Hz, J ¼ 9.0 Hz, 1H), 6.19
(s, 1H), 4.68 (t, J ¼ 6.0 Hz, 1H), 4.20 (d, J ¼ 6.0 Hz, 2H), 3.81 (s, 3H),
yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼ 7.78 (d, J ¼ 7.7 Hz, 2H),
7.55 (dt, J ¼ 0.9 Hz, J ¼ 7.9 Hz, 1H), 7.37 (d, J ¼ 7.7 Hz, 2H), 7.35
(dd, J ¼ 0.9 Hz, J ¼ 8.4 Hz, 1H), 7.26 (ddd, J ¼ 1.1 Hz, J ¼ 7.2 Hz,
J ¼ 8.4 Hz, 1H), 7.12 (ddd, J ¼ 1.1 Hz, J ¼ 7.1 Hz, J ¼ 7.9 Hz, 1H), 6.34
(s, 1H), 5.40 (m, 1H), 5.10 (m, 1H), 4.51 (s, 2H), 3.85 (s, 3H), 3.83
(m, 2H), 3.72 (dd, J ¼ 1.2 Hz, J ¼ 6.8 Hz, 1H), 2.48 (s, 3H); 13C NMR
3.62 (m, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 154.1,
143.7, 136.2, 133.8, 133.3, 129.7, 127.2, 127.1, 112.3, 109.9, 102.2, 101.9,
55.8, 39.9, 29.8, 21.5; MS (ES): m/z ¼ 345.0 [M þ H]þ, 367.1
[M þ Na]þ.
(100 MHz, CDCl3):
d
¼ 143.9, 138.2, 135.6, 132.7, 131.4, 130.0, 129.7
4.2.6. N-((1-Benzyl-indol-2-yl)methyl)-4-
methylbenzenesulfonamide (4e)
(2C), 127.3 (2C), 126.7, 122.3, 120.3, 119.9, 109.4, 103.7, 57.9, 45.1,
43.7, 33.7, 21.5; MS (ES): m/z ¼ 385.1 [M þ H]þ, 407.0 [M þ Na]þ.
Yield ¼ 89%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
white solid. m.p. ¼ 152.3e152.8 ꢀC; 1H NMR (400 MHz, CDCl3):
4.3.3. (E)-8a
d
¼ 7.72 (d, J ¼ 8.3 Hz, 2H), 7.61 (d, J ¼ 7.7 Hz,1H), 7.27e7.31 (m, 6H),
Yield ¼ 64%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
7.23 (ddd, J ¼ 1.2 Hz, J ¼ 8.2 Hz, J ¼ 9.5 Hz, 1H), 7.16 (ddd,
J ¼ 1.2 Hz, J ¼ 6.9 Hz, J ¼ 7.8 Hz, 1H), 6.94 (m, 2H), 6.40 (s, 1H), 5.33
(s, 2H), 4.66 (t, J ¼ 6.0 Hz, 1H), 4.17 (d, J ¼ 6.0 Hz, 2H), 2.42
white viscous wax. 1H NMR (400 MHz, CDCl3):
d
¼
7.77
(d, J ¼ 8.3 Hz, 2H), 7.54 (d, J ¼ 8.1 Hz, 1H), 7.36 (d, J ¼ 8.3 Hz, 2H),
7.28e7.34 (m, 2H), 7.23 (ddd, J ¼ 1.4 Hz, J ¼ 7.2 Hz, J ¼ 9.2 Hz, 1H),
7.11 (ddd, J ¼ 0.9 Hz, J ¼ 7.2 Hz, J ¼ 7.9 Hz, 1H), 6.32 (s, 1H), 5.27
(m, 2H), 4.52 (s, 2H), 3.86 (s, 3H), 3.66e3.70 (m, 4H), 2.48 (s, 3H);
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 143.7, 137.8, 137.5, 136.1,
133.5, 129.7, 128.7, 127.5, 127.1,1, 25.9, 122.4, 120.7, 119.9, 109.7,
103.3, 46.4, 39.8, 21.5; MS (ES): m/z ¼ 391.1 [M þ H]þ, 413.0
[M þ Na]þ.
13C NMR (100 MHz, CDCl3):
d
¼ 143.8, 138.0, 135.9, 133.4, 132.8,
129.9, 127.4, 126.9, 127.4, 126.9, 125.4, 122.2, 120.5, 119.8, 109.2,
103.9, 62.6, 48.6, 44.8, 30.1, 21.6; MS (ES): m/z ¼ 385.1 [M þ H]þ,
407.0 [M þ Na]þ.
4.2.7. N-((1-Allyl-indol-2-yl)methyl)-4-methylbenzenesulfonamide
(4f)
Yield ¼ 87%. Flash chromatography (c-Hex:AcOEt ¼ 80:20);
4.3.4. (Z)-8b
white solid. m.p. ¼ 112.5e113.1 ꢀC; 1H NMR (400 MHz, CDCl3):
Yield ¼ 69%. Flash chromatography (c-Hex:AcOEt ¼ 80:20);
d
¼ 7.74 (d, J ¼ 8.0 Hz, 2H), 7.52 (d, J ¼ 7.5 Hz,1H), 7.21 (m, 2H), 7.10 (t,
yellowish solid. m.p. ¼ 139.6e140.5 ꢀC; 1H NMR (400 MHz, CDCl3):
J ¼ 7.5 Hz, 2H), 6.33 (s, 1H), 5.91 (m, 1H), 5.10 (d, J ¼ 10.1 Hz, 1H),
d
¼ 7.76 (d, J ¼ 8.0 Hz, 2H), 7.50 (d, J ¼ 1.8 Hz, 1H), 7.39 (d, J ¼ 8.0 Hz,
4.71e4.82 (m, 4H), 4.22 (d, J ¼ 6.1 Hz, 2H), 2.43 (s, 3H); 13C NMR
2H), 7.25 (d, J ¼ 9.0 Hz, 1H), 7.50 (dd, J ¼ 2.1 Hz, J ¼ 9.0 Hz, 1H), 6.28
(s, 1H), 5.45 (m, 1H), 5.04 (m, 1H), 4.47 (s, 1H), 3.89 (d, J ¼ 6.3 Hz,
1H), 3.83 (s, 3H), 3.73 (d, J ¼ 7.3 Hz, 1H), 2.48 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼ 143.7, 137.4, 136.2, 133.4, 133.3(2C), 133.2,
129.7 (2C), 127.1, 122.1, 120.6, 119.8, 116.3, 109.6, 102.9, 45.3, 39.7,
21.5; MS (ES): m/z ¼ 341.0 [M þ H]þ, 363.0 [M þ Na]þ.
(100 MHz, CDCl3):
d
¼ 144.0, 136.6, 135.6, 134.1, 131.7, 130.0 (2C),
127.7, 127.3 (2C), 126.0, 125.5, 122.6, 119.7, 110.4, 103.2, 57.9, 44.9,
4.3. General procedure for N-allylic alkylation of tosyl amides
3/4 (7/8)
43.8, 30.3, 21.6; MS (ES): m/z ¼ 419.0 [M þ H]þ, 441.0 [M þ Na]þ.
4.3.5. (Z)-8c
To a solution of 3 (0.3 mmol) in THF (3 mL), NaH (60% in mineral
oil, 0.33 mmol) was added at 0 ꢀC and the mixture was stirred
for 30 min at room temperature. Then corresponding allyl bromide
(Z)-C (0.36 mmol) was added and the reaction was stirred at
reflux temperature overnight. Then, after cooling at rt, 5 mL of H2O
were added and the organic materials extracted with AcOEt
(3 ꢂ 5 mL). The collected organic layers were washed with H2O
(6 ꢂ 5 mL), dried over Na2SO4 and concentrated to leave a yellow
slurry. Flash column chromatography (SiO2) eluting with a cHex/
ethyl acetate mixture.
Yield ¼ 62%. Flash chromatography (c-Hex:AcOEt ¼ 80:20);
Yellowish oil. 1H NMR (400 MHz, CDCl3):
d
¼ 7.77 (d, J ¼ 8.0 Hz, 2H),
7.38 (d, J ¼ 8.0 Hz, 2H), 7.32 (m, 1H), 7.23 (d, J ¼ 8.4 Hz, 1H), 7.08
(d, J ¼ 8.4 Hz, 1H), 6.25 (m, 1H), 5.38 (m, 1H), 5.11 (m, 1H), 4.47
(s, 2H), 3.83 (d, J ¼ 5.3 Hz, 1H), 3.82 (s, 3H), 3.71 (dd, J ¼ 1.4 Hz,
J ¼ 7.2 Hz, 1H), 2.48 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 147.8, 136.6, 135.6, 132.6, 131.3, 129.9 (2C), 129.1, 127.4 (2C),
126.9, 126.2, 124.0, 119.9, 109.1, 103.1, 57.8, 45.2, 43.6, 30.1, 26.9,
21.3; MS (ES): m/z ¼ 399.0 [M þ H]þ, 421.1 [M þ Na]þ.
Deprotection of the alcohol group: silyl-ether was dissolved in
THF, then TBAF (1.5 eq. with respect to 3/4) was added and the
mixture was stirred for 4 h at room temperature. After that the
4.3.6. (Z)-8d
Yield ¼ 66%. Flash chromatography (c-Hex:AcOEt ¼ 60:40);
White wax. 1H NMR (400 MHz, CDCl3):
d
¼ 7.76 (d, J ¼ 8.0 Hz, 2H),

M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
345
7.36 (d, J ¼ 8.0 Hz, 2H), 7.22 (d, J ¼ 9.2 Hz, 1H), 9.98 (d, J ¼ 2.4 Hz,
1H), 6.90 (dd, J ¼ 1.8 Hz, J ¼ 9.2 Hz, 1H), 6.25 (s, 1H), 5.38e5.43
(m, 1H), 5.06e5.11 (m, 1H), 4.45 (s, 3H), 3.85 (d, J ¼ 7.2 Hz, 1H), 3.82
(s, 3H), 3.79 (s, 2H), 3.71 (dd, J ¼ 1.4 Hz, J ¼ 6.4 Hz, 1H), 2.47 (s, 3H),
was stirred at room temperature overnight. Then the insoluble
black powder was filtered off (CAUTION!) with celite, washed with
CH2Cl2 (10 mL) and the organics evaporated under reduced pres-
sure. The crude (R)-10f was finally purified by flash chromatog-
1.79 (br, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 154.2, 143.8, 135.5,
raphy (c-Hex: AcOEt ¼ 8:2). Yield ¼ 85%. Ee ¼ 74%. [
a
]
¼ ꢁ35.1
D
133.5, 133.0, 131.4, 129.9 (2C), 129.6, 127.3 (2C), 126.9, 112.5, 110.1,
103.1, 101.9, 68,5, 57.8, 55.8, 45.0, 43.6, 27.7; MS (ES): m/z ¼ 415
[M þ H]þ, 437 [M þ Na]þ.
(c ¼ 0.35, CHCl3), [lit. (R)-10f, ee ¼ 88%, [
a
]
D
¼ ꢁ79.1 (c ¼ 1.0,
CHCl3)]. See ref. [4] for analytical details.
4.5. Representative procedure for the enantioselective gold-
catalyzed synthesis of tetrahydro- -carbolines 12
4.3.7. (Z)-8e
b
Yield ¼ 73%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
yellowish solid. m.p. ¼ 71.6e72.3 ꢀC. 1H NMR (400 MHz, CDCl3):
A flamed two-neck round bottom flask, under nitrogen atmo-
sphere, was charged with 1 mL of anhydrous CH2Cl2, 6.2 mg of L10
(5.6 mmol) and 3.2 mg of [AuCl(DMS)] (11.2 mmol). The mixture was
stirred for 30 min at rt, then the solvent removed in vacuum and
replaced with anhydrous toluene (1 mL). After covering the flask
d
¼ 7.67 (d, J ¼ 8.3 Hz, 2H), 7.57 (dt, J ¼ 0.8 Hz, J ¼ 7.9 Hz, 1H),
7.23e7.29 (m, 6H), 7.19 (ddd, J ¼ 1.4 Hz, J ¼ 7.0 Hz, J ¼ 9.4 Hz, 1H),
7.12 (ddd, J ¼ 0.9 Hz, J ¼ 7.0 Hz, J ¼ 7.9 Hz, 1H), 7.00 (m, 2H), 4.06
(s, 1H), 5.5 (s, 2H), 5.44 (m, 1H), 5.09 (m, 1H), 4.39 (s, 2H), 3.87
(d, J ¼ 6.8 Hz, 1H), 3.72 (d, J ¼ 6.8 Hz, 1H), 2.42 (s, 3H); 13C NMR
with an aluminum foil, 2.8 mg of AgOTf (11.2
mmol) were added and
(100 MHz, CDCl3):
d
¼ 143.7, 138.1, 137.6, 135.5, 132.5, 131.6, 129.8
the mixture led to stir for 30 min, the desired alcohol 8 (56 m
mol)
(2C), 128.6, 127.3 (2C), 127.1, 127.0, 126.1, 125.9, 122.5, 120.4, 120.0,
110.0, 104.7, 104.6, 57.7, 46.4, 44.6, 43.6, 21.5; MS (ES): m/z ¼ 461.1
[M þ H]þ, 483.0 [M þ Na]þ.
was added and the mixture stirred for the desired time (24e48 h)
in the dark. Evaporation of the volatiles led to a crude mixture
that was directly charged into a flash chromatographic column for
purification.
4.3.8. (Z)-8f
Yield ¼ 74%. Flash chromatography (c-Hex:AcOEt ¼ 70:30);
4.5.1. (S)-9-Methyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-pyrido[3,4-
b]indole 12a
yellowish oil. 1H NMR (400 MHz, CDCl3):
d
¼ 7.77 (d, J ¼ 8.2 Hz, 2H),
7.55 (dt, J ¼ 1.0 Hz, J ¼ 7.9 Hz, 1H), 7.37 (d, J ¼ 8.2 Hz, 2H), 7.33 (ddd,
J ¼ 0.8 Hz, J ¼ 1.8 Hz, J ¼ 8.3 Hz, 1H), 7.23 (ddd, J ¼ 1.1 Hz, J ¼ 7.0 Hz,
J ¼ 8.2 Hz, 1H), 7.11 (ddd, J ¼ 1.1 Hz, J ¼ 7.0 Hz, J ¼ 7.9 Hz, 1H), 6.37
(s, 1H), 6.00 (m, 1H), 5.77 (m, 1H), 5.11 (m, 2H), 4.92 (m, 3H), 4.45
(s, 2H), 3.90 (m, 2H), 3.75 (d, J ¼ 7.0 Hz, 2H), 2.86 (s, 3H); 13C NMR
Yield ¼ 75%. ee ¼ 80%. Flash chromatography (c-Hex:AcOEt ¼
90:10); white solid. m.p. ¼ 171.0e172.0 ꢀC; [
a
]
¼ þ5.0 (c ¼ 0.8,
D
CHCl3). HPLC analysis: OD column (225 nm), 40 ꢀC, method: n-
Hex:IPA ¼ 80:20, flow 1.0 mL/min, t(R) ¼ 10.3 min, t(S) ¼ 11.8 min. 1H
NMR (400 MHz, CDCl3):
d
¼ 7.76 (d, J ¼ 8.0 Hz, 2H), 7.49 (d, J ¼ 8.0 Hz,
(100 MHz, CDCl3):
d
¼ 143.7, 137.6, 135.6, 133.3, 131.6, 129.8 (2C),
1H), 7.32 (d, J ¼ 8.0 Hz, 1H), 7.24 (dt, J ¼ 0.9 Hz, J ¼ 8.2 Hz, 1H), 7.16
(ddd, J ¼ 1.2 Hz, J ¼ 7.2 Hz, J ¼ 8.3 Hz, 1H), 7.04 (ddd, J ¼ 0.9 Hz,
J ¼ 7.2 Hz, J ¼ 8.0 Hz,1H), 5.87 (ddd, J ¼ 8.0 Hz, J ¼ 10.0 Hz, J ¼ 17.1 Hz,
1H), 5.22 (m, 2H), 4.32 (d, J ¼ 14.1 Hz, 1H), 4.29 (d, J ¼ 14.1 Hz, 1H),
3.75 (m, 1H), 3.59 (s, 3H), 3.45 (dd, J ¼ 4.6 Hz, J ¼ 11.8 Hz, 1H), 3.87
(dd, J ¼ 6.0 Hz, J ¼ 11.8 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz,
127.3, 126.9 (2C), 126.8, 122.2, 120.3, 119.8, 116.2, 109.8, 107.7, 104.2,
57.7, 45.4, 44.4, 43.5, 21.4; MS (ES): m/z ¼ 411.1 [M þ H]þ, 433.0
[M þ Na]þ.
4.3.9. (Z)-5l
Synthesized through procedure 4.3, employing indolyl malo-
nate 1 and (Z)-1-MsO-4-methoxybut-2-ene.[25a] Yield ¼ 56%.
Flash chromatography (c-Hex:AcOEt ¼ 80:20); light brown oil. 1H
CDCl3):
d
¼ 143.8, 138.3, 137.3, 133.7, 130.1, 129.8 (2C), 127.7 (2C),
126.0, 121.5, 119.3, 119.1, 116.8, 108.9, 108.8, 49.4, 42.8, 38.2, 31.9,
29.5; MS (ES): m/z ¼ 367.1 [M þ H]þ, 389.0 [M þ Na]þ.
NMR (400 MHz, CDCl3):
d
¼ 8.12 (bs, 1H), 7.56 (d, J ¼ 8.2 Hz, 1H),
7.34 (d, J ¼ 8.0 Hz, 1H), 7.11e7.17 (m, 2H), 7.00 (bs, 1H), 5.67 (m, 2H),
4.15 (d, J ¼ 7.6 Hz, 4H), 3.89 (d, J ¼ 5.6 Hz, 2H), 3.45 (s, 2H), 3.28
(s, 3H), 2.72 (d, J ¼ 6.8 Hz, 2H), 1.22 (t, J ¼ 7.1 Hz, 6H); 13C NMR
4.5.2. (S)-6-Chloro-9-methyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-
pyrido[3,4-b]indole 12b
Yield ¼ 93%. Ee ¼ 79%. Flash chromatography (c-Hex:AcOEt ¼
(100 MHz, CDCl3):
d
¼ 171.3, 135.8, 129.9, 128.2, 126.6, 123.1, 123.0,
90:10); Yellow wax. [
a
]
¼ þ3 (c ¼ 1.2, CHCl3). HPLC analysis: AD
D
122.0, 119.4, 111.0, 110.0, 68.2, 61.3, 58.4, 53.0, 30.7, 27.9, 13.9;
column (214 nm), 40 ꢀC, method: n-Hex:IPA ¼ 80:20, flow 1.0 mL/
MS (ES): m/z ¼ 374.1 [M þ H]þ.
min, t(R) ¼ 12.8 min, t(R) ¼ 16.6 min. 1H NMR (400 MHz, CDCl3):
d
¼ 7.76 (d, J ¼ 8.0 Hz, 2H), 7.62 (d, J ¼ 7.7 Hz, 1H), 7.34 (d, J ¼ 8.0 Hz,
4.3.10. (Z)-5m
2H), 7.17 (d, J ¼ 8.8 Hz, 1H), 7.13 (dd, J ¼ 1.6 Hz, J ¼ 8.8 Hz, 1H), 5.85
(ddd, J ¼ 8.0 Hz, J ¼ 10.0 Hz, J ¼ 17.2 Hz, 1H), 5.26 (m, 2H), 4.33 (d,
J ¼ 15.1 Hz, Hz, 1H), 4.27 (d, J ¼ 15.1 Hz, 1H), 3.71 (m, 1H), 3.60 (s,
3H), 3.48 (dd, J ¼ 5.1 Hz, J ¼ 11.9 Hz, 1H), 3.20 (dd, J ¼ 6.4 Hz,
Synthesized through procedure 4.3, employing indolyl malo-
nate 1 and (Z)-4-bromobut-2-enyl acetate.[25b] Yield ¼ 58%. Flash
chromatography (c-Hex:AcOEt ¼ 75:25); yellow oil. 1H NMR
(400 MHz, CDCl3):
d
¼ 8.18 (bs, 1H), 7.55 (d, J ¼ 7.9 Hz, 1H), 7.57
J ¼ 11.9 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼ 143.9,
d
(d, J ¼ 8.4 Hz, 1H), 7.07e7.17 (m, 2H), 6.98 (d, J ¼ 2.4 Hz, 1H), 5.69
(m, 2H), 4.52 (d, J ¼ 5.1 Hz, 2H), 4.14 (d, J ¼ 7.1 Hz, 4H), 3.44 (s, 2H),
2.73 (d, J ¼ 5.9 Hz, 2H), 2.02 (s, 3H), 1.21 (t, J ¼ 7.1 Hz, 6H); 13C NMR
137.8, 135.9, 135.7, 133.5, 131.6, 130.2, 129.8 (2C), 127.8 (2C), 125.1,
121.4, 118.6, 109.8, 108.6, 49.3, 42.7, 38.1, 26.9, 26.7; MS (ES): m/
z ¼ 401.0 [M þ H]þ, 433.0 [M þ Na]þ.
(100 MHz, CDCl3):
d
¼ 171.1, 135.8, 128.4, 128.1, 127.1, 123.1, 123.0,
121.9, 119.3, 118.7, 11.0, 109.8, 61.2, 60.3, 58.4, 30.7, 30.6, 28.0, 13.9;
4.5.3. (S)-6,9-Dimethyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-pyrido
[3,4-b]indole 12c
MS (ES): m/z ¼ 402.2 [M þ H]þ.
Yield ¼ 75%. Ee ¼ 80%. Flash chromatography (c-Hex:AcOEt ¼
4.4. Detemination of the absolute configuration of 10b
90:10); White solid. m.p. ¼ 171.4e171.9 ꢀC; [
a
]
¼ þ2 (c ¼ 0.8,
D
CHCl3). HPLC analysis: AD column (214 nm), 40 ꢀC, method: n-
Hex:IPA ¼ 80:20, flow 0.7 mL/min, t(S) ¼ 12.2 min, t(R) ¼ 14.1 min. 1H
The vinyl-carbazole (S)-10b (ee: 80%, 0.10 mmol) was added to
a suspension of Pd(OH)2 (20 mol%) in anhydrous MeOH (4 mL). The
apparatus was connected to a balloon filled with hydrogen in order
to maintain a reducing atmosphere (z1 atm). The dark mixture
NMR (400 MHz, CDCl3):
J ¼ 8.3 Hz, 2H), 7.28 (m, 1H), 7.15 (d, J ¼ 8.2 Hz, 1H), 7.01
d
¼ 7.77 (d, J ¼ 8.3 Hz, 2H), 7.35 (d,
(dd, J ¼ 1.4 Hz, J ¼ 8.3 Hz, 1H), 5.90 (ddd, J ¼ 7.9 Hz, J ¼ 10.9 Hz,

346
M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
J ¼ 17.1 Hz, 1H), 5.25 (m, 2H), 4.34 (dd, J ¼ 1.4 Hz, J ¼ 14.5 Hz, 1H),
4.27 (dd, J ¼ 1.4 Hz, J ¼ 14.5 Hz, 1H), 3.76 (m, 1H), 3.59 (s, 3H), 3.44
(dd, J ¼ 4.7 Hz, J ¼ 11.7 Hz, 1H), 3.27 (dd, J ¼ 5.9 Hz, J ¼ 11.7 Hz, 1H),
Appendix A. Supplementary material
CCDC 794470 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2.44 (s, 3H), 2.42 (s, 3H); 13C- NMR (100 MHz, CDCl3):
d
¼ 143.8,
138.5, 135.7, 133.7, 130.1, 129.8 (2C), 128.6, 127.6 (2C), 126.2, 123.0,
118.7, 116.7, 108.5, 108.3, 49.4, 42.8, 38.1, 29.5, 21.5, 21.4; MS (ES): m/
z ¼ 381.2 [M þ H]þ, 403.1 [M þ Na]þ.
References
4.5.4. (S)-6-Methoxy-9-methyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-
pyrido[3,4-b]indole 12d
[1] (a) A.S.K. Hashmi, Angew. Chem. Int. Ed. 44 (2005) 6990;
(b) A.S.K. Hashmi, G.J. Hutchings, Angew. Chem. Int. Ed. 45 (2006) 7896;
(c) A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180;
Yield ¼ 61%. Ee ¼ 76%. Flash chromatography (c-Hex:AcOEt ¼
85:15); white solid; m.p. ¼136e165 ꢀC; [
a
]
¼ þ7.6 (c ¼ 0.5, CHCl3).
D
(d) A.S.K. Hashmi, Catal. Today 122 (2007) 211;
HPLC analysis: OD column (214 nm), 40 ꢀC, method: n-
Hex:IPA ¼ 85:15, flow 1.0 mL/min, t(R) ¼ 12.4 min, t(S) ¼ 13.8 min. 1H
(e) A. Fürstner, O.D. Davies, Angew. Chem. Int. Ed. 46 (2007) 3410;
(f) A.S.K. Hashmi, M. Rudolph, Chem. Soc. Rev. 37 (2008) 1766;
(g) H.C. Shen, Tetrahedron 64 (2008) 3885;
(h) R. Skouta, C.-J. Li, Tetrahedron 64 (2008) 4917;
(i) A. Arcadi, Chem. Rev. 108 (2008) 3266;
(j) D.J. Gorin, B.D. Sherry, F.D. Toste, Chem. Rev. 108 (2008) 3351;
(k) N. Bongers, N. Krause, Angew. Chem. Int. Ed. 47 (2008) 2178;
(l) A.S.K. Hashmi, Chem. Aust. 76 (2009) 7;
(m) P. Belmont, E. Parker, Eur. J. Org. Chem. (2009) 6075;
(n) N.D. Shapiro, F.D. Toste, Synlett (2010) 675;
NMR (400 MHz, CDCl3):
d
¼ 7.76 (d, J ¼ 8.0 Hz, 2H), 7.34 (d,
J ¼ 8.0 Hz, 2H), 7.15 (d, J ¼ 9.2 Hz, 1H), 6.96 (d, J ¼ 2.4 Hz, 1H), 6.84
(dd, J ¼ 2.4 Hz, J ¼ 9.2 Hz,1H), 5.84e5.93 (m,1H), 5.30 (dt, J ¼ 1.6 Hz,
J ¼ 16.8 Hz, 1H), 5.20 (dd, J ¼ 2.4 Hz, J ¼ 10.8 Hz, 1H), 4.29 (s, 2H),
3.82 (s, 3H), 3.70e3.75 (m, 1H), 3.59 (s, 3H), 3.50 (dd, J ¼ 5.2 Hz,
J ¼ 12.4 Hz, 1H), 2.23 (dd, J ¼ 7.2 Hz, J ¼ 12.4 Hz, 1H); 13C NMR
(o) S. Wang, G. Zhang, L. Zhang, Synlett (2010) 692.
[2] (a) R.A. Widenhoefer, Chem. Eur. J. 14 (2008) 5382;
(b) S. Sengupta, X. Shi, Chem. Cat. Chem. 2 (2010) 609.
[3] Z. Zhang, S.D. Lee, R.A. Widenhoefer, J. Am. Chem. Soc. 131 (2009) 5372.
[4] M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 48 (2009) 9533.
[5] For general review see: (a) B.M. Trost, D.L. Van Vraken, Chem. Rev. 96 (1996)
395;
(b) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 33 (2000) 336;
(c) B.M. Trost, M.L. Crawley, Chem. Rev. 103 (2003) 2921.
[6] (a) M. Bandini, A. Melloni, F. Piccinelli, R. Sinisi, S. Tommasi, A. Umani-Ronchi,
J. Am. Chem. Soc. 128 (2006) 1424;
(100 MHz, CDCl3):
(2C),127.6 (2C),126.4,116.7,111.1,109.4,108.3,101.5, 55.9, 49.4, 42.8,
d
¼ 153.8, 143.8, 138.3, 133.7, 132.6, 130.7, 129.8
38.2, 31.9, 26.9; MS (ES): m/z ¼ 397.1 [M þ H]þ.
4.5.5. (S)-9-Benzyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-pyrido
[3,4-b]indole 12e
Yield ¼ 95%. Ee ¼ 70%. Flash chromatography (c-Hex:AcOEt ¼
95:5). Light brown oil. [
a
]
¼ ꢁ4 (c ¼ 1.1, CHCl3). HPLC analysis: OD
D
column (214 nm), 40 ꢀC, method: n-Hex:IPA ¼ 80:20, flow 0.7 mL/
(b) H.Y. Cheung, W.-Y. Yu, F.L. Lam, T.T.-L. Au-Yeung, Z. Zhou, T.H. Chan,
A.S.C. Chan, Org. Lett. 9 (2007) 4295;
min, t(S) ¼ 14.7 min, t(R) ¼ 17.4 min. 1H NMR (400 MHz, CDCl3):
(c) W.-B. Liu, H. He, L.-X. Dai, S.-L. You, Org. Lett. 10 (2008) 1815;
(d) L.M. Stanley, J.F. Hartwig, Angew. Chem. Int. Ed. 48 (2009) 7841;
(e) Q.-F. Wu, H. He, W.-B. Liu, S.-L. You, J. Am. Chem. Soc. 132 (2010) 11418.
[7] B.M. Trost, J. Quancard, J. Am. Chem. Soc. 128 (2006) 6314.
[8] The metal-assisted activation of the allylic alcohol prevents the formation of
an allylic carbocationic species (SN1-type mechanism) that would preclude
any stereochemical control in the reaction course.
[9] M. Bandini, A. Eichholzer, M. Tragni, A. Umani-Ronchi, Angew. Chem. Int. Ed.
47 (2008) 3238.
[10] For general review of catalytic asymmetric FC-type alkylation see: (a)
K.A. Jørgensen, Synthesis (2003) 1117;
d
¼ 7.66 (d, J ¼ 8.5 Hz, 2H), 7.56 (d, J ¼ 8.4 Hz, 1H), 7.23e7.29 (m, 7H),
7.15 (ddd, J ¼ 1.3 Hz, J ¼ 8.3 Hz, J ¼ 9.1 Hz, 1H), 7.08 (ddd, J ¼ 1.3 Hz,
J ¼ 6.9 Hz, J ¼ 7.3 Hz, 1H), 7.00 (m, 2H), 5.92 (m, 1H), 5.25e5.32 (m,
2H), 5.22 (s, 2H), 4.22 (s, 2H), 3.79 (m,1H), 3.48 (d, J ¼ 6.8 Hz,1H), 3.25
(d, J ¼ 6.8 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼ 143.7,
d
139.3, 137.1, 136.9, 133.8, 133.2, 130.1, 129.7 (2C), 128.9 (2C), 127.6,
127.6 (2C),126.2 (2C),125.9,121.8,119.5,119.2,109.6,109.4, 49.3, 46.8,
42.8, 38.2, 26.9; MS (ES): m/z ¼ 461.1 [M þ H]þ, 483.0 [M þ Na]þ.
(b) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. Int. Ed. 43 (2004)
550;
(c) T.B. Poulsen, K.A. Jørgensen, Chem. Rev. 108 (2008) 2903;
(d) Y.-F. Sheng, A.-J. Zhang, X.-J. Zheng, S.-L. You, Chin. J. Org. Chem. 28 (2008)
605;
4.5.6. (S)-9-Allyl-2-tosyl-4-vinyl-2,3,4,9-tetrahydro-pyrido[3,4-b]
indole 12f
Yield ¼ 71%. Ee ¼ 78%. Flash chromatography (c-Hex:AcOEt ¼
(e) M. Bandini, A. Umani-Ronchi (Eds.), Catalytic Asymmetric Friedel-Crafts
Alkylations, Wiley-VCH, Weinheim, 2009;
90:10). White sticky solid. [
a
]
¼ þ1.2 (c ¼ 1.3, CHCl3). HPLC anal-
D
ysis: OD column (210 nm), 40 ꢀC, method: n-Hex:IPA ¼ 80:20, flow
(f) M. Rueping, B.J. Nachtsheim, Beilstein J. Org. Chemisrty 6 (2010) Nꢀ 6;
(g) M. Bandini, Chem. Soc. Rev., in press.
1.0 mL/min, t(R) ¼ 7.6 min, t(S) ¼ 11.1 min. 1H NMR (400 MHz, CDCl3):
[11] M. Bandini, M. Tragni, Org. Biomol. Chem. 7 (2009) 1501.
[12] (a) H.-J. Knölker, K.R. Reddy, Chem. Rev. 102 (2002) 4303;
(b) A. González-Gómez, G. Domínguez, J. Pérez-Castells, Tetrahedron 65
(2009) 3378.
[13] C. Samoj1owicz, M. Bieniek, K. Grela, Chem. Rev. 109 (2009) 3708.
[14] A.J. Kochanowska-Karamyan, M.T. Hamann, Chem. Rev. 110 (2010) 4489.
[15] For general reviews see: (a) M. Hesse, Alkaloids. Nature’s Curse or Blessing?
Wiley-VCH, New York, 2002;
(b) M.A. Walters, in: G.W. Gribble, J.A. Joule (Eds.), Progress in Heterocyclic
Chemistry, vol. 15, Pergamon, Amsterdam, 2003, pp. 1e36;
(c) M. Chrzanowska, M.D. Rozwadowska, Chem. Rev. 104 (2004) 3341.
[16] (a) D.T. Jones, G.D. Artman, R.M. Williams, M. Robert, Tetrahedron. Lett. 48
(2007) 1291;
(b) X. Han, R.A. Widenhoefer, Org. Lett. 8 (2006) 3801.
[17] A variant of the two-step methodology reported by Ruano was utilized,
see J.L. García Ruano, J. Alemán, M. Belén Cid, A. Parra, Org. Lett. 7 (2005)
179.
d
¼ 7.75 (d, J ¼ 8.4 Hz, 2H), 7.53 (d, J ¼ 8.1 Hz, 1H), 7.34 (d, J ¼ 8.4 Hz,
2H), 7.24 (d, J ¼ 8.1 Hz, 1H), 7.17 (ddd, J ¼ 1.4 Hz, J ¼ 7.2 Hz,
J ¼ 8.3 Hz, 1H), 7.07 (ddd, J ¼ 1.4 Hz, J ¼ 7.2 Hz, J ¼ 7.9 Hz, 1H), 5.90
(m, 2H), 5.31 (m, 1H), 5.20 (m, 1H), 5.14 (ddd, J ¼ 1.6 Hz, J ¼ 2.6 Hz,
J ¼ 10.3 Hz, 1H), 4.87 (ddd, J ¼ 1.7 Hz, J ¼ 2.7 Hz, J ¼ 17.7 Hz, 1H),
4.62 (m, 2H), 4.30 (s, 2H), 3.78 (m, 1H), 3.49 (dd, J ¼ 4.7 Hz,
J ¼ 11.8 Hz, 1H), 3.26 (dd, J ¼ 6.1 Hz, J ¼ 11.8 Hz, 1H), 2.35 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d
¼ 143.8, 138.3, 136.8, 133.9, 132.8, 129.9
(2C), 129.8, 127.9 (2C), 127.6, 126.2, 121.6, 119.4, 119.2, 116.8, 109.4,
109.2, 49.3, 45.6, 42.6, 38.1, 29.7; MS (ES): m/z ¼ 393.1 [M þ H]þ,
415.0 [M þ Na]þ.
[18] (a) M.P. Muñoz, J. Adrio, J.C. Carretero, A.M. Echavarren, Organomet 24 (2005)
1293;
(b) C. Liu, R.A. Widenhoefer, Org. Lett. 9 (2007) 1935.
[19] M. Bandini, A. Eichholzer, A. Gualandi, T. Quinto, D. Savoia, Chem. Cat. Chem. 2
(2010) 661.
[20] V. Cadierno, S.E. Garcia-Garrido, J. Gimeno, N. Nerba, Chem. Commun. (2005)
4086.
[21] Z. Zhang, C. Liu, R.E. Kinder, X. Han, H. Qian, R.A. Widenhoefer, J. Am. Chem.
Soc. 128 (2006) 9066.
Acknowledgements
Acknowledgment is made to the MIUR (Rome), Università di
Bologna, and Fondazione del Monte di Bologna e Ravenna. We also
thank Dr. M. Scalone F. Hoffmann-La Roche AG for the generous gift
of MeOBIPHEP and Federico Dosi for part of the experimental work.

M. Bandini et al. / Journal of Organometallic Chemistry 696 (2011) 338e347
347
[22] H. Huang, R. Peters, Angew. Chem. Int. Ed. 48 (2009) 604.
[23] (a) SMART & SAINT Software Reference Manuals, Version 5.051 (Windows NT
Version). Bruker Analytical X-ray Instruments Inc., Madison, WI, 1998;
(b) G.M. Sheldrick, SADABS, program for empirical absorption correction.
University of Göttingen, Germany, 1996;
[24] G.M. Sheldrick, Structure Determination Package SHELXTL plus Version 5.1
(Windows NT version). Bruker Analytical XrayInstruments Inc., Madison, WI,
1998.
[25] For analogous behavior on the gold catalyzed synthesis of saturated hetero-
cyclic compounds see:
(c) A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo,
A. Guagliardi, A.G.G. Moliterni, G. Polidori, R. Spagna, J. Appl, Crystallogr 32
(1999) 115.
(a) 1,4-diol/NaH/MeI/DMF (35%, unoptimized), methylether/MsCl/TEA/DCM
(61%, unoptimized). (b) M. Mitchell, L. Qaio, C.-H. Wong, Adv. Synth. Catal. 343
(2001) 596.